Impact of Late Dosing on Testosterone Suppression with 2 Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere. An Analysis of United States Clinical Data.

PURPOSE: Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate. MATERIALS AND METHODS: We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated. RESULTS: A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month. CONCLUSIONS: Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

Evolving understanding and categorization of prostate cancer: preventing progression to metastatic castration-resistant prostate cancer: RADAR IV.

INTRODUCTION To interpret data and update the traditional categorization of prostate cancer in order to help treating clinicians make more informed decisions. These updates include guidance regarding how to best use next generation imaging (NGI) with the caveat that the new imaging technologies are still a work in progress. MATERIALS AND METHODS: Literature review. RESULTS: Critical goals in prostate cancer management include preventing or delaying emergence of distant metastases and progression to castration-resistant disease. Pathways for progression to metastatic castration-resistant prostate cancer (mCRPC) involve transitional states: nonmetastatic castration-resistant prostate cancer (nmCRPC), metastatic hormone-sensitive prostate cancer (mHSPC), and oligometastatic disease. Determination of clinical state depends in part on available imaging modalities. Currently, fluciclovine and gallium-68 (68Ga) prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) are the NGI approaches with the most favorable combination of availability, specificity, and sensitivity. PET imaging can be used to help guide treatment selection in most patients. NGI can help determine patients who are candidates for new treatments, most notably (next-generation androgen antagonists, eg, apalutamide, enzalutamide, darolutamide), that can delay progression to advanced disease. CONCLUSIONS: It is important to achieve a consensus on new and more easily understood terminology to clearly and effectively describe prostate cancer and its progression to health care professionals and patients. It is also important that description of disease states make clear the need to initiate appropriate treatment. This may be particularly important for disease in transition to mCRPC.

A Clinician's Guide to Next Generation Imaging in Patients With Advanced Prostate Cancer (RADAR III).

PURPOSE: The advanced prostate cancer therapeutic landscape has changed dramatically in the last several years, resulting in improved overall survival of patients with castration naïve and castration resistant disease. The evolution and development of novel next generation imaging techniques will affect diagnostic and therapeutic decision making. Clinicians must navigate when and which next generation imaging techniques to use and how to adjust treatment strategies based on the results, often in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience. MATERIALS AND METHODS: The RADAR (Radiographic Assessments for Detection of Advanced Recurrence) III Group convened to offer guidance on the use of next generation imaging to stage prostate cancer based on available data and clinical experience. The group also discussed the potential impact of next generation imaging on treatment options based on earlier detection of disease. RESULTS: The group unanimously agreed that progression to metastatic disease is a seminal event for patient treatment. Next generation imaging techniques are able to detect previously undetectable metastases, which could redefine the phases of prostate cancer progression. Thus, earlier systemic or locally directed treatment may positively alter patient outcomes. CONCLUSIONS: The RADAR III Group recommends next generation imaging techniques in select patients in whom disease progression is suspected based on laboratory (biomarker) values, comorbidities and symptoms. Currently 18F-fluciclovine and 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography are the next generation imaging agents with a favorable combination of availability, specificity and sensitivity. There is ongoing research of additional next generation imaging technologies, which may offer improved diagnostic accuracy and therapeutic options. As next generation imaging techniques evolve and presumably result in improved global accessibility, clinician ability to detect micrometastases may be enhanced for decision making and patient outcomes.

Approach to Androgen Deprivation in the Prostate Cancer Patient with Pre-existing Cardiovascular Disease.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is a mainstay of treatment for advanced prostate cancer. Several studies have reported an association between ADT and an increase in cardiovascular events, especially in those receiving gonadotropin-releasing hormone (GnRH) agonists compared to GnRH antagonists. We review the body of literature reporting the association of ADT and cardiovascular morbidity, and discuss the proposed mechanism of cardiovascular disease due to ADT including metabolic changes that may promote atherosclerosis and local hormonal effects that may increase plaque rupture and thrombosis. RECENT FINDINGS: GnRH agonists appear to increase the risk of cardiovascular morbidity by 20-25% in men on these agents compared those who do not receive ADT. GnRH antagonists may appear to have halve this risk while improving PSA progression-free survival. GnRH antagonists may be superior to GnRH agonists for patients with significant cardiovascular disease, significant metastatic disease burden, or severe lower urinary tract symptoms.

Avoiding obsolescence in advanced prostate cancer management: a guide for urologists.

Prostate cancer is one of the most common cancers diagnosed in men in the USA and 20­30% of men treated for localised prostate cancer will fail therapy and develop advanced prostate cancer. More drugs have been approved for the treatment of advanced prostate cancer in the past 3 years than in the past three decades, and each drug has its own mechanism of action and, often, unique monitoring requirements. As the treatment landscape for men with advanced prostate cancer is undergoing significant expansion, the roles of both oncologists and urologists are shifting, and the decision for the urologist to treat vs refer requires early assessment to identify which patients are candidates for these novel treatments and the monitoring of patients for tolerability, response, and potential side-effects. Given these rapid changes, the authors of this review met in January 2013 and again in April 2013 to discuss the current challenges facing urologists in adopting these new treatments into their own practices. Here, we provide a brief overview of advanced prostate cancer medical therapies approved in the past decade, the necessary monitoring procedures and early detection methods needed to safely and effectively manage patients receiving these therapies, and our recommendations for applying these new therapies within different models of urology practice, such that urologists can remain an integral component of their patient's care once he has transitioned into advanced prostate cancer

Impact of prostate cancer on sexual relationships: a longitudinal perspective on intimate partners' experiences.

INTRODUCTION: In this prospective study of localized prostate cancer patients and their partners, we analyzed how partner issues evolve over time, focusing on satisfaction with care, influence of cancer treatment, and its impact on relationship with patient, cancer worry, and personal activities. AIMS: Our study aims were twofold: (i) to determine whether the impact of treatment on patients and partners moderate over time and (ii) if receiving surgery (i.e., radical prostatectomy) influences partner issues more than other treatments. METHODS: Patients newly diagnosed with localized prostate cancer and their female partners were recruited from three states to complete surveys by mail at three time points over 12 months. MAIN OUTCOME MEASURES: The four primary outcomes assessed in the partner analysis included satisfaction with treatment, cancer worry, and the influence of cancer and its treatment on their relationship (both general relationship and sexual relationship). RESULTS: This analysis included 88 patient-partner pairs. At 6 months, partners reported that cancer had a negative impact on their sexual relationship (39%--somewhat negative and 12%--very negative). At 12 months, this proportion increased substantially (42%--somewhat negative and 29%--very negative). Partners were significantly more likely to report that their sexual relationship was worse when the patient reported having surgery (P = 0.0045, odds ratio = 9.8025, 95% confidence interval 2.076-46.296). A minority of partners reported significant negative impacts in other areas involving their personal activities (16% at 6 months and 25% at 12 months) or work life (6% at 6 months, which increased to 12% at 12 months). CONCLUSION: From partners' perspectives, prostate cancer therapy has negative impact on sexual relationships and appears to worsen over time.

Improved performance of SPECT-CT In-111 capromab pendetide by correlation with diffusion-weighted magnetic resonance imaging for identifying metastatic pelvic lymphadenopathy in prostate cancer.

PURPOSE: To preliminarily evaluate the potential for an improvement in diagnostic performance by a combined interpretation of In-111 capromab pendetide single photon emission computed tomography (SPECT) including computed tomography (CT) image fusion with magnetic resonance diffusion-weighted imaging (MR-DWI) for identifying prostate cancer in pelvic lymph nodes thru correlation with histopathology. MATERIALS AND METHODS: This institutional approved, retrospective study identified patients with available histopathology of lymph nodes removed at the time of radical prostatectomy and who had undergone staging with In-111 capromab pendetide SPECT-CT and/or pelvic MRI (including DWI). The performance of In-111 capromab pendetide SPECT for identifying malignant lymph nodes was assessed. Subsequently, a combined reading of In-111 capromab pendetide SPECT and prostate MRI with DWI was performed and the performance assessed. RESULTS: 18 patients underwent In-111 capromab pendetide SPECT-CT. Of these, 12 patients had also undergone imaging with MR-DWI. In-111 capromab pendetide SPECT-CT had a sensitivity of 40.0% and specificity of 96.7% for identification of malignant lymph nodes. However, In-111 capromab pendetide SPECT-CT combined with MRI with DWI had a sensitivity of 88.9% and specificity of 98.5%. CONCLUSIONS: The addition of MR-DWI to the interpretation of In-111 capromab pendetide SPECT-CT may increase the sensitivity for detecting malignant lymph nodes in prostate cancer. Future prospective evaluation of combined In-111 capromab pendetide SPECT-CT and MR-DWI is indicated and may improve clinical evaluation of nodal disease in prostate cancer.

Burden among partner caregivers of patients diagnosed with localized prostate cancer within 1 year after diagnosis: an economic perspective.

PURPOSE: Informal care plays an important role in the overall care for people with cancer. This study estimates lost productivity and informal caregiving and associated costs among partner caregivers of localized prostate cancer patients within 1 year after diagnosis. METHODS: We applied data from the Family and Cancer Therapy Selection study, a three-wave self-administered survey among patients diagnosed with localized prostate cancer and their partner caregivers in multiple clinics in the USA. Time spent was measured by the sum of working hours lost, informal caregiving hours performed, and hours spent on household chores. The national median income for women 55 years or older was used to calculate costs associated with the time spent using the opportunity cost method. Descriptive and bivariate analyses were conducted. RESULTS: The average working hours decreased from 14.0 h/week (SD = 17.6) to 10.9 h/week (SD = 15.9), without a significant change in responsibility/intensity at work. The mean annual time spent on informal caregiving and household chores was 65.9 h/year (SD = 172.4) and 76.2 h/year (SD = 193.3), respectively. The mean annual economic burden among partner caregivers was US$6,063 (range US$571-US$47,105) in 2009 dollars accounted for by a mean of 276.2 h (range 26-2,146) in the study sample. The time spent on informal caregiving and household chores varied by patient and caregiver characteristics. CONCLUSIONS: Pilot estimates on non-medical economic burden among partner caregivers (spouses) during the initial phase of the treatment provide important information for comprehensive estimation of disease burden and can be used in cost-effectiveness analyses of prostate cancer interventions.

Detection of mitochondrial deoxyribonucleic acid alterations in urine from urothelial cell carcinoma patients.

Our study aims at understanding the timing and nature of mitochondrial deoxyribonucleic acid (mtDNA) alterations in urothelial cell carcinoma (UCC) and their detection in urine sediments. The entire 16.5 kb mitochondrial genome was sequenced in matched normal lymphocytes, tumor and urine sediments from 31 UCC patients and compared to different clinical stages and histological grades. The mtDNA content index was examined in all the specimens. Sixty-five percent (20/31) of the patients harbored at least 1 somatic mtDNA mutation. A total of 25 somatic mtDNA mutations were detected, which were more frequent in the respiratory complex coding regions (Complex I, III, IV and V) of the mtDNA and significantly affected respiratory Complex III compared to the other complexes (p = 0.021-0.039). Compared to Stage Ta, mtDNA mutation was higher in Stage T1 and significantly higher in Stage T2 (p = 0.01) patients. MtDNA mutation was also significantly higher (p = 0.04) in Stage T2 compared to Stage T1 patients. Ninety percent (18/20) of the patients harboring mtDNA mutation in the tumor also had mutation in their urine sediments. Eighty percent (20/25) of the tumor-associated mtDNA mutations was detectable in the urine sediments. Compared to the normal lymphocytes, the mtDNA content increased significantly in the tumor (p = 0.0013) and corresponding urine sediments (p = 0.0025) in 19/25 (76%) patients analyzed. Our results indicate that mtDNA alterations occur frequently in progressive stages of UCC patients and are readily detectable in the urine sediments. MtDNA mutations appear to provide a promising tool for developing early detection and monitoring strategies for UCC patients.

Willingness to pay for prostate cancer treatment among patients and their family members at 1 year after diagnosis.

OBJECTIVES: To explore an alternative approach to quantifying the burden of side effects at 1 year after treatment for prostate cancer among both patients and their partners. METHODS: We analyzed data from 75 couples in the Family and Cancer Therapy Selection study. Paired patients and family members were independently asked about their willingness to pay (WTP) for a hypothetical new treatment that cures prostate cancer without side effects if they could reconsider their treatment decision by indicating the maximum amount they would be willing to pay given 11 separate "bids" ranging from $0 to $1500 per month. Descriptive and regression analyses were conducted for patients and family members controlling for sociodemographic characteristics and health status; Spearman correlations were also examined. RESULTS: Among 75 couples analyzed, the income-adjusted mean WTP estimates per month were $400.8 (standard error [SE] $54.3) for patients and $650.2 (SE 72.2) for family members. The WTP between patients and family members was correlated (Pearson ρ 0.30; P = 0.01). After adjusting for covariates, the adjusted mean WTP per month was $588.1 (SE 65.77) for patients and $819.4 (SE 74.33) for family members. Wanting to avoid side effects at baseline predicted higher WTP for patients (P = 0.010). Experiencing sexual side effects was predictive of higher WTP for family members (P = 0.047). CONCLUSIONS: Fairly high WTP amounts for a hypothetical treatment without side effects suggests that patients and their partners are experiencing important burdens 1 year after treatment. The higher amounts partners are willing to pay and the correlation with sexual side effects suggest that they are perceptive of significant treatment burdens.

Provider and partner interactions in the treatment decision-making process for newly diagnosed localized prostate cancer.

OBJECTIVE: • To evaluate the degree to which the partners of prostate cancer patients participate in the shared decision-making process with the patients' providers during the time between diagnosis and initiating treatment. PATIENTS AND METHODS: • We recruited patients with newly diagnosed local-stage prostate cancer and their partners to complete take-home surveys after biopsy but before initiating treatment at urology practices in three states. • We asked partners to describe their roles in the decision-making process, including participation in clinic visits, and perceptions of encouragement from providers to participate in the treatment decision-making process. We also asked partners to rate their satisfaction with the patients' providers. RESULTS: • Family members of 80% of newly diagnosed patients agreed to participate; most (93%) were partners (i.e. spouses or significant others). Most partners (93%) had direct contact with the patients' physicians. • Among the partners who had contact with providers, most (67%) were very satisfied with the patients' providers and 80% indicated that the doctor encouraged them to participate in the treatment decision. Overall, 91% of partners reported very frequent discussions with their loved one about the pending treatment decision, and 69% reported that their role was to help the patient make a decision. • In multivariate models, provider encouragement of partner participation was associated with higher partner satisfaction (odds ratio 3.4, 95% CI 1.4-8.4) and an increased likelihood of partners reporting very frequent discussions with their loved one (odds ratio 6.1, 95% CI 1.3-27.7). CONCLUSIONS: • Partners often attended clinic visits and were very involved in discussions about treatment options with both loved ones and providers. • Provider encouragement of participation by partners greatly facilitates shared decision-making between patients and partners.

Patient preferences and urologist recommendations among local-stage prostate cancer patients who present for initial consultation and second opinions.

OBJECTIVES: This study describes urologist recommendations for treatment among local-stage prostate cancer patients presenting for initial management consultations versus second opinions. We hypothesized that urologists present a wider range of management recommendations and are less likely to consider the patient preference during the initial consultation. METHODS: Newly diagnosed local-stage prostate cancer patients and their urologists participated in a survey at urology practices in three states. The urologist's survey included questions about the patient's clinical status, treatments discussed and recommended, and factors that influenced the urologist's recommendations. RESULTS: Of the 238 eligible patients, 95 men presented for an initial consultation, and 143 men presented for a second opinion. In multivariate analysis, urologists recommended 0.52 more treatments (standard error 0.19, P<0.001) during an initial consultation as opposed to a second opinion. The proportion recommending surgery increased from 71-91% (initial consultation versus second opinion setting). Among initial consultations, 59% had low-risk disease, and urologists' recommendations included surgery (80%), external radiation (38%), brachytherapy (seeds) (52%), and active surveillance (25%). Of the 54% with low-risk disease in a second opinion consultation, urologists' recommendations included surgery (90%), external radiation (16%), brachytherapy (14%), and active surveillance (16%). CONCLUSIONS: In second opinion settings urologists discussed fewer treatment options and recommended surgery more often. These findings also applied to men with low-risk prostate cancer.

Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer.

Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

Chronic calcific pancreatitis: combination ERCP and extracorporeal shock wave lithotripsy for pancreatic duct stones.

BACKGROUND: Chronic pancreatitis is commonly associated with debilitating abdominal pain, in part due to pancreatic duct obstruction. Pancreatic stones are often impossible to extract from the duct with endoscopic retrograde cholangiopancreatography alone. Extracorporeal shock wave lithotripsy (ESWL) is commonly used for fragmentation of obstructing nephrolithiasis and has demonstrated effectiveness in management of pancreatic stones. Our aim was to examine the outcomes of the first 30 patients with symptomatic pancreatic stones treated with a combination of ESWL and endoscopic therapies. METHODS: Patients with symptomatic chronic calcific pancreatitis referred for ESWL (2005-2009) were included. Technical success of ESWL was defined as a) stone fragmentation sufficient to allow extraction of main duct stones at ERCP or b) absence of the targeted main pancreatic duct stones on follow-up radiography. Clinical success of ESWL was defined by Patient Global Impression of Improvement (PGII) score of at least slightly improved. RESULTS: Thirty patients underwent ESWL. One patient was excluded due to adenocarcinoma. Technical success was achieved in 17/29 (58.6%) patients. 25 (86.2%) patients were available for follow-up (median 35 months, range 3-52 months). Fifteen of twenty-five (60%) patients experienced clinical improvement (10 patients very much improved), but there was no significant reduction in the proportion taking narcotics (50% before vs. 44.4% after ESWL). Pancreatic surgery has been avoided to date in 16 (64%) of the 25 patients. CONCLUSIONS: A multidisciplinary approach, combining ERCP and ESWL, to painful obstructing pancreatic duct stones provided symptomatic improvement and allowed pancreatic surgery to be avoided in the majority of patients.

Evaluation of modern pathological criteria for positive margins in radical prostatectomy specimens and their use for predicting biochemical recurrence.

OBJECTIVES: To assess the interpretation of modern criteria for evaluating surgical margins (SMs), by examining the incidence of positive SMs (PSMs) and subsequent biochemical recurrence in a single-surgeon series of radical prostatectomy (RP) at two institutions, as the criteria for determining PSMs after RP are subject to individual interpretation, and this might explain some of the variability in biochemical recurrence rates with different rates of PSMs. PATIENTS AND METHODS: We reviewed 301 consecutive perineal RPs by one surgeon (T.K.) at Emory University Hospital (EUH) and the Medical University of South Carolina (MUSC), with each pathology department using modern criteria to evaluate the SMs. The SM status and biochemical recurrence (BCR) were analysed, the latter defined as a prostate-specific antigen level of > or =0.2 ng/mL. RESULTS: There were 158 perineal RPs at EUH followed by 143 at MUSC. PSMs were reported in 39 patients (24.7%) at EUH, whereas six (4.2%) were positive at MUSC. The overall BCR rates were similar between the groups, but BCR within margin-positive cases was 100% at MUSC vs 25.6% at EUH (P < 0.01). The presence of tumour at <1 mm from the margin did not increase the rate of BCR compared to those with obvious negative SMs (P = 0.731). CONCLUSION: In this single-surgeon series, using the same criteria to evaluate the SMs resulted in significantly different PSM rates and margin-positive BCR rates between the institutions. Although the reason for these differences is difficult to determine, the study shows clearly that tumour within 1 mm of the margin should not be classified as margin-positive.

Functional analysis of the host defense peptide Human Beta Defensin-1: new insight into its potential role in cancer.

Although it is known that innate immunity is key for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have anti-tumor activity. Human Beta Defensin-1 (hBD-1), an important component of the innate immune response, is lost at high frequencies in malignant prostatic tissue, while high levels of expression are maintained in adjacent benign regions. In prostate carcinoma, frequent genetic alterations occur in the 8p22-23 region and several studies indicate there may be multiple tumor suppressor genes present within this region. The high incidence of loss of hBD-1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may play a role in tumor suppression. To gain insight as to its function in prostate cancer, hBD-1 was cloned and ectopically expressed in four prostate cancer cell lines. Induction of hBD-1 expression resulted in a decrease in cellular growth in DU145 and PC3 cells. However, hBD-1 has no effect on the growth of androgen receptor (AR) positive LNCaP prostate cancer cells, but was again growth suppressive to PC3 cells with ectopic AR expression (PC3/AR+). hBD-1 also caused rapid induction of cytolysis and caspase-mediated apoptosis in DU145 and PC3 prostate cancer cells. Although the regulation of hBD-1 was not addressed in this study, our preliminary data demonstrated that the pathways involved may include cMYC and PAX2. Data presented here are the first to provide evidence of its potential role in prostate cancer cell death.

Upregulated expression of complement inhibitory proteins on bladder cancer cells and anti-MUC1 antibody immune selection.

Membrane complement inhibitors (CD46, CD55 and CD59) are upregulated in some human cancers indicating that they play a role in immune evasion. We investigated complement inhibitor expression in bladder cancer and examined the hypothesis that selective pressure of an antibody response (anti-MUC1) results in the upregulated expression of complement inhibitors on tumor cells. Paired samples of tumor and normal tissue from 22 bladder cancer patients were analyzed for expression of MUC1, CD46, CD55 and CD59, and matched serum samples analyzed for anti-MUC1 IgM and IgG levels. Relationships between anti-MUC1 antibody levels and complement inhibitor expression were investigated. MUC1 mRNA was upregulated in 86% of tumor samples. CD46 was upregulated in 77%, CD55 in 55% and CD59 in 59% of tumors. Low titer anti-MUC1 IgM was detected in normal human sera, but was elevated in 41% of the bladder cancer patients. Anti-MUC1 IgG was virtually absent from normal sera, but present in 32% of the cancer patients. There was a direct relationship between anti-MUC1 antibody titer and expression level of complement inhibitors. Analysis of the correlation of each antibody with the expression of each complement inhibitor by Spearman's rank test revealed a strong correlation between both anti-MUC1 IgM and IgG levels and increased expression of CD46 and CD55, and combined anti-MUC1 IgM/IgG levels correlated with increased expression of all 3 complement inhibitors. In conclusion, the data demonstrate upregulated complement inhibitor expression and the presence of an anti-MUC1 antibody response in bladder cancer patients and support the hypothesis of antibody-mediated immune selection.

Acid ceramidase inhibition: a novel target for cancer therapy.

During the last decade, sphingolipid deregulation, namely the balance between the pro-apoptotic molecule ceramide and the anti-apoptotic sphingolipid sphingosine-1-phosphate, has emerged as an important factor in cancer pathology and resistance to therapy. Thus, our research has been focused on developing drugs that are able to restore normal sphingolipid balance, precisely through increasing the levels of ceramide and decreasing sphingosine-1-phosphate. Particularly, inhibition of the ceramide metabolizing enzyme acid ceramidase, whose over-expression in cancer cells has been implicated in resistance to treatment, is proving to be an efficient and promising strategy. In this review, we consider our recent work with acid ceramidase inhibitors, in combination with radiation or gene therapy as a sensitizer that enhance cancer therapy.

Salvage options for biochemical recurrence after primary therapy for prostate cancer.

Despite excellent success rates with radical prostatectomy and radiotherapy for the treatment of prostate cancer, a significant number of patients will experience a rise in their serum prostate specific antigen (PSA) level. A variety of salvage options in this scenario have been investigated and the choice to pursue surveillance, single therapy or combination therapy depends on clinical assessment of risk and location of tumor recurrence. After radical prostatectomy, for example, patients with low risk local disease may not require secondary therapy or may benefit from salvage radiotherapy. Those with higher risk disease, based on PSA kinetics and tumor pathology may require systemic androgen deprivation therapy (ADT) with or without radiotherapy. Local recurrence after radiotherapy has the options of cryotherapy, brachytherapy or salvage surgery. ADT can also be applied in these patients at high risk of disease progression and cancer-specific mortality. Risk assessment in these settings is paramount as all secondary therapy options for prostate cancer have potential side effects that may significantly affect quality of life. We review the literature and discuss the current methods of risk assessment and the treatment options in prostate cancer once primary therapy fails.